Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents

Low, Woon Kai; Li, Jing; Zhu, Mingzhao; Kommaraju, Sai Shilpa; Shah-Mittal, Janki; Hull, Kenneth G.; Liu, Jun O.; Romo, Daniel

doi:10.1016/j.bmc.2013.11.046

Cited by 39 publications

(73 citation statements)

References 34 publications

(59 reference statements)

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“…As a result, this has paved the way for the generation of synthetic derivatives of PatA, including DMDA-PatA, which has been found to possess anti-neoplastic activity in several human cancer cell lines and xenograft mouse models [131]. While these derivatives have the advantage of possessing a simpler and more efficient synthesis strategy, there has yet to be a synthetic analog exhibiting improved potency over PatA [133]. In addition, it is also possible that structural modifications to PatA can alter the specificity of the resulting compound.…”

Section: Pateamine Amentioning

confidence: 98%

“…Also, early studies of PatA characterized it as an immunosuppressive compound that inhibits IL-2 production [137]. Interestingly, although PatA is roughly 5-10 times more potent than DMDA-PatA as an inhibitor of translation, it is approximately 5 times weaker as a suppressor of IL-2 production [133]. In addition, PatA can inhibit nonsense mediated decay as it is known to also target eIF4A2I, a DEAD-box helicase that shares approximately 65% amino acid identity with eIF4A1/II and is responsible for forming the helicase core of the exon junction complex [128].…”

Section: Pateamine Amentioning

confidence: 98%

“…In addition, it is also possible that structural modifications to PatA can alter the specificity of the resulting compound. As an example, DMDA-PatA has been shown to also suppress IL-2 production as well as inhibit DNA synthesis [131,133] Furthermore, there are still questions regarding the specificity of PatA. Affinity chromatography with immobilized PatA identified not only eIF4A1 and eIF4A2 as cellular targets of PatA, but also the serine/ threonine kinase receptor associated protein (STRAP), which has been implicated in cap-independent translation [126,134,135].…”

Section: Pateamine Amentioning

confidence: 98%

See 2 more Smart Citations

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

Chu

Pelletier

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Section: Pateamine Amentioning

confidence: 98%

Section: Pateamine Amentioning

confidence: 98%

Section: Pateamine Amentioning

confidence: 98%

See 1 more Smart Citation

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

Chu

Pelletier

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…We next examined SAMD9 protein behavior under cellular stress conditions that either stimulated (sodium arsenate [SA] treatment at 1 mM for 1 h) or were independent of (desmethyl desamino pateamine A derivative [DMDA-PatA] treatment at 1 M for 1 h) eIF2␣ phosphorylation (12,13). When cells were stimulated with SA, an oxidative stress stimulus, along with other markers of SGs, SAMD9 nucleated into the SGs (Fig.…”

mentioning

confidence: 99%

SAMD9 Is an Innate Antiviral Host Factor with Stress Response Properties That Can Be Antagonized by Poxviruses

Liu

McFadden

2015

J Virol

100

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We show that SAMD9 is an innate host antiviral stress response element that participates in the formation of antiviral granules. Poxviruses, myxoma virus and vaccinia virus specifically, utilize a virus-encoded host range factor(s), such as a member of the C7L superfamily, to antagonize SAMD9 to prevent granule formation in a eukaryotic initiation factor 2␣ (eIF2␣)-independent manner. When SAMD9 is stimulated due to failure of the viral antagonism during infection, the resulting antiviral granules exhibit properties different from those of the canonical stress granules. Poxviruses are enveloped large double-stranded DNA (dsDNA) viruses that replicate exclusively in the cytoplasm. Numbers of immunoregulatory factors are encoded in the poxvirus genome to antagonize multiple host defense pathways at all levels. We previously showed that a targeted knockout of M062R, an essential host range factor of the C7L superfamily in the myxoma virus (MYXV) genome, led to a profound defect of viral replication in cells from all species tested, including human, rabbit, and primate cells (1). Viral M062 antagonizes cellular SAMD9 during viral infection through direct protein-protein interactions, and knocking down the expression of SAMD9 in human cells lifts the block of late gene expression from MYXV-M062R-null infection (1). To investigate the antiviral functions of SAMD9, we examined the cellular localization of this host protein during permissive wild-type and nonpermissive MYXV-M062R-null infection by immunofluorescence (IF) staining. We observed that, during MYXV-M062R-null infection, SAMD9 formed a granule structure in the cytoplasm. The accumulation of concentrated SAMD9 was detected as early as 7 h postinfection (p.i.). By 18 h p.i., 91.0% (Ϯ6.2% standard deviation [SD]) of infected cells showed SAMD9 granules which were then mostly concentrated near the viral factories (Fig. 1A). During permissive infection by wild-type MYXV that expressed M062 protein, SAMD9 was observed to become distributed throughout the cells, which was also distinct from the exclusive cytoplasmic localization of SAMD9 in uninfected cells. We further investigated the SAMD9 granules and found that they are not conventional stress granules (SGs), as they cannot be dispersed by cycloheximide treatment (not shown) in a manner similar to that seen with the antiviral granules previously described, which form after infection with E3L-knockout vaccinia virus (VACV) (2). On the other hand, several hallmark markers of SGs, such as rasGTPase-activating protein-binding protein 1 (G3BP1) (3) (Fig. 1), T-cell intracellular antigen 1-related protein (TIAR) (4), USP10 (5), and key translation initiation factors such as eukaryotic initiation factor 4G (eIF4G) (6) (Fig. 1B), were readily detected surrounding the viral factories colocalized with the SAMD9 granules in infection by MYXV-M062-null. However, in addition to the SAMD9 granules that overlap G3BP1 staining, SAMD9 staining can be detected outside the viral factories. The polyclonal SAMD9 antibody used in thi...

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“…Recently, different research teams have used this initiation factor as therapeutic target in cancer or the small 40S ribosomal subunit, 4 binds eIF4G through eIF3 to carry out the scanning of the mRNA to the start codon, 5 and the full 80S ribosome is subsequently formed. Then the GDP-eIF2 complex is released and gives rise to the elongation phase during viral infections and have obtained promising and interesting results [30,31].…”

Section: The Eif4a Factor and Its Role In Translation Initiationmentioning

confidence: 99%

Eukaryotic initiation factor 4A (eIF4A) during viral infections

2019

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The helicase eIF4A is part of the cellular eIF4F translation initiation complex. The main functions of eIF4A are to remove secondary complex structures within the 5′-untranslated region and to displace proteins attached to mRNA. As intracellular parasites, viruses regulate the processes involved in protein synthesis, and different mechanisms related to controlling translation factors, such as eIF4A, have been found. The inhibitors of this factor are currently known; these substances could be used in the near future as part of antiviral pharmacological therapies in instances of replication cycles in which eIF4A is required. In this review, the particularities of how some viruses make use of this initiation factor to synthesize their proteins are discussed.

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Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents

Cited by 39 publications

References 34 publications

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

SAMD9 Is an Innate Antiviral Host Factor with Stress Response Properties That Can Be Antagonized by Poxviruses

Eukaryotic initiation factor 4A (eIF4A) during viral infections

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